Meloxicam hydrochloride

The crystal structure determined for meloxicam hydrochloride is not isomorphous with the known structure of the hydrobromide analogue.

The title salt, C 14 H 14 N 3 O 4 S 2 + ÁCl À [systematic name: 2-(4-hydroxy-2-methyl-1,1dioxo-1,2-benzothiazine-3-amido)-5-methyl-1,3-thiazol-3-ium chloride] is the hydrochloride derivative of meloxicam, a drug used to treat pain and inflammation in rheumatic disorders and osteoarthritis. Although its molecular structure is similar to that previously reported for the hydrobromide analogue, both salts are not isomorphous. Different crystal structures originate from a conformational modification, arising from a degree of rotational freedom for the thiazolium ring in the cations. By taking as a reference the conformation of meloxicam, the thiazolium ring is twisted by 10.96 and À16.70 in the hydrochloride and hydrobromide salts, while the 1,2-benzothiazine core is a rigid scaffold. This behaviour could explain why meloxicam is a polymorphous compound.

Structure description
Meloxicam [abbreviated hereafter as MX; systematic name: 4-hydroxy-2-methyl-N-(5methyl-1,3-thiazol-2-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide] is an achiral benzothiazine drug, practically insoluble in water at physiological pH (Luger et al., 1996). This molecule was patented in 1977, and is currently classified as an antipyretic and nonsteroidal anti-inflammatory medication, used for the management of pain and inflammation associated with rheumatoid arthritis and osteoarthritis, in adults and children. In some countries, it has also been approved for use in veterinary medicine. The crystallization of meloxicam is a 'difficult art' (Ś niechowska et al., 2021), since four neat polymorphic forms are known, along with one hydrated form (Coppi et al., 2003;Freitas et al., 2017). So far, only the triclinic form I and the hydrated form were structurally characterized by X-ray diffraction (Luger et al., 1996;Fabiola et al., 1998;Fedorov et al., 2019). Actually, the formula of MXÁH 2 O is not well defined: for the reported structure, the water data reports molecule is disordered over two general positions, with occupancies reported as 0.53 (3) and 0.63 (3).
Among the many meloxicam salts characterized by X-ray diffraction, the hydrobromide was deposited as a CSD communication (Tumanov et al., 2011;CSD refcode: XATJAF). MXÁHBr crystallizes in space group P2 1 /c. The thiazole group is protonated, in such a way that a doubleacceptor hydrogen bond is formed with the bromide ion accepting links from the thiazolium and amide NH groups, to form a common R 1 2 (6) ring motif with the thiazolium and amide NH groups as donors. The conformation for HMX + is close to that observed for neutral MX, owing to an intramolecular hydrogen bond between the enol group in the 1,2benzothiazine core and the carbonyl group of the amide functionality, which gives the common S(6) motif. We have now determined the structure of the hydrochloride salt, MXÁHCl, which also crystallizes in space group P2 1 /c, although with different unit-cell parameters. The molecular structure of MXÁHCl is similar to that of MXÁHBr, including the same intramolecular O-HÁ Á ÁO and intermolecular N-HÁ Á ÁCl hydrogen bonds ( Fig. 1; Table 1, entries 1-3). Molecules are however packed in different ways in both salts, as corroborated by their simulated powder diffraction patterns, which are clearly different (Fig. 2). If the nature of the anion, Cl À or Br À , is not taken into account, MXÁHBr and MXÁHCl can thus be described as polymorphic forms crystallizing in a single space group.
A close examination of the conformation of the cations, and a comparison with the neutral molecule MX (Fabiola et al., 1998; CSD refcode: SEDZOQ) rationalizes this behaviour.
Assuming that the 1,2-benzothiazine core is a rigid moiety, an overlay between HMX + in both salts and MX shows that the thiazolium ring has some degree of rotational freedom. Taking MX as reference, the HMX + cation has its thiazolium ring twisted by 10.96 in MXÁHCl and by À16.70 in MXÁHBr (Fig. 3). This rotation over a range of ca 25 is sufficient to enable the formation of distinct secondary intermolecular contacts (Table 1, entries 4 and 5), which, in turn, alter the packing of the cations in the crystal. By widening this behaviour to meloxicam, for which the rotation of the thiazole group is less restrained, since no R 1 2 (6) ring motif involving an halide ion is present, one would assume that the rich poly- Table 1 Hydrogen-bond geometry (Å , ). Symmetry codes: (i) x; y þ 1; z; (ii) Àx þ 1; y À 1 2 ; Àz þ 1 2 .

Figure 2
Simulated powder X-ray diffraction patterns for MXÁHBr (top, pattern calculated using the deposited Cif file for XATJAF; Tumanov et al., 2011) and MXÁHCl (bottom). Patterns were calculated with Mercury (Macrae et al., 2020), assuming the Cu K radiation. Molecular structures are represented along with their patterns.

Figure 3
Overlay between meloxicam (grey), MXÁHBr (red) and MXÁHCl (green), calculated with Mercury (Macrae et al., 2020). The fits were carried out using atoms belonging to the 1,2-benzothiazine core (14 atoms), while the amide and thiazole groups were kept free. The r.m.s. deviations for the fits are better than 0.04 Å . For the structure of the neutral molecule MX, which has been reported three times, refcode SEDZOQ was retained (Fabiola et al., 1998), in order to have all models at room temperature. For clarity, halide anions are omitted, as well as H atoms bonded to C atoms. Note that in MX, the thiazole ring is not protonated.

Figure 1
Molecular structure of the title compound, with displacement ellipsoids at the 50% probability level for non-H atoms. Dashed lines represent intramolecular hydrogen bonds (

Synthesis and crystallization
Meloxicam hydrochloride was unintentionally crystallized while screening slurry co-crystallizations using derivatives of (S)--methylbenzylamine or l-proline as coformers. In some experiments, an amount of a 0.02 N HCl solution was added to the slurry, for the purpose of modifying the pH of the medium. Single crystals of the MXÁHCl salt were recovered from these slurries.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2.